外部静态 EF 对 5-HT1A 受体构象转变的影响:分子动力学模拟研究。

IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Lulu Guan , Jingwang Tan , Bote Qi , Yukang Chen , Meng Cao , Qingwen Zhang , Yu Zou
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引用次数: 0

摘要

血清素受体亚型 1A(5-HT1AR)是 G 蛋白偶联受体(GPCR)家族中的一种,与多种神经系统疾病有关。在分子水平上了解 5-HT1AR 的激活和失活机制对于发现治疗多种疾病的新型疗法至关重要。最近,人们越来越认识到外部电场(EF)在影响生物大分子结构和活性方面的作用。在这项研究中,我们利用分子动力学(MD)模拟研究了 5-HT1AR 活性态的构象特征,并探讨了 0.02 V/nm 的外部静态电场对 5-HT1AR 活性态的影响。结果表明,5-HT1AR 的活性状态保持了原生结构,而外加静态外场因子导致了 5-HT1AR 结构的改变,尤其是诱导了跨膜螺旋 6(TM6)的内向移动。此外,它还扰乱了与 CWxP、DRY、PIF 和 NPxxY 动机中的激活相关的构象转换,从而使其倾向于非活性构象。我们还发现,EF 导致了 5-HT1AR 偶极矩的整体增加,包括 TM6 和关键氨基酸。对 TM6 构象特性的分析表明,在 EF 条件下,二级结构发生了变化,溶剂暴露减少。在 EF 条件下,5-HT1AR 与膜脂双层的相互作用也发生了改变。我们的研究结果揭示了外部 EF 诱导 5-HT1AR 构象转变的分子机制,为基于结构的 EF 应用于 GPCRs 的前景提供了潜在的新见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Effects of an external static EF on the conformational transition of 5-HT1A receptor: A molecular dynamics simulation study

Effects of an external static EF on the conformational transition of 5-HT1A receptor: A molecular dynamics simulation study

The serotonin receptor subtype 1A (5-HT1AR), one of the G-protein-coupled receptor (GPCR) family, has been implicated in several neurological conditions. Understanding the activation and inactivation mechanism of 5-HT1AR at the molecular level is critical for discovering novel therapeutics in many diseases. Recently there has been a growing appreciation for the role of external electric fields (EFs) in influencing the structure and activity of biomolecules. In this study, we used molecular dynamics (MD) simulations to examine conformational features of active states of 5-HT1AR and investigate the effect of an external static EF with 0.02 V/nm applied on the active state of 5-HT1AR. Our results showed that the active state of 5-HT1AR maintained the native structure, while the EF led to structural modifications in 5-HT1AR, particularly inducing the inward movement of transmembrane helix 6 (TM6). Furthermore, it disturbed the conformational switches associated with activation in the CWxP, DRY, PIF, and NPxxY motifs, consequently predisposing an inclination towards the inactive-like conformation. We also found that the EF led to an overall increase in the dipole moment of 5-HT1AR, encompassing TM6 and pivotal amino acids. The analyses of conformational properties of TM6 showed that the changed secondary structure and decreased solvent exposure occurred upon the EF condition. The interaction of 5-HT1AR with the membrane lipid bilayer was also altered under the EF. Our findings reveal the molecular mechanism underlying the transition of 5-HT1AR conformation induced by external EFs, which offer potential novel insights into the prospect of employing structure-based EF applications for GPCRs.

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来源期刊
Biophysical chemistry
Biophysical chemistry 生物-生化与分子生物学
CiteScore
6.10
自引率
10.50%
发文量
121
审稿时长
20 days
期刊介绍: Biophysical Chemistry publishes original work and reviews in the areas of chemistry and physics directly impacting biological phenomena. Quantitative analysis of the properties of biological macromolecules, biologically active molecules, macromolecular assemblies and cell components in terms of kinetics, thermodynamics, spatio-temporal organization, NMR and X-ray structural biology, as well as single-molecule detection represent a major focus of the journal. Theoretical and computational treatments of biomacromolecular systems, macromolecular interactions, regulatory control and systems biology are also of interest to the journal.
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